Quinazoline derivatives

ABSTRACT

Compounds of the formula I in which R, X, L 2  and A 1 -A 6  have the meanings indicated in Claim  1 , are PI3K inhibitors and can be employed, inter alia, for the treatment of autoimmune diseases, inflammation, cardiovascular diseases, neurodegenerative diseases and tumours.

BACKGROUND OF THE INVENTION

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

The present invention relates to compounds and the use thereof for themodulation, in particular for the inhibition, of the activity orfunction of the phosphoinositide 3′-OH kinase family (hereinafter PI3kinases), advantageously PI3Kα, PI3Kδ, PI3Kβ and/or PI3Kγ. The presentinvention advantageously relates to the use of quinoxaline derivativesin the treatment of one or more disease states selected from: autoimmunedisorders, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, blood platelet aggregation, cancer, spermmotility, transplant rejection, graft rejection and lung injuries.

Cell membranes provide a large store of secondary messengers that can beenlisted in a variety of signal transduction pathways. As regards thefunction and regulation of effector enzymes in phospholipid signallingpathways, these enzymes generate secondary messengers from the membranephospholipid pools. Class I PI3 kinases (for example PI3Kα) aredual-specificity kinase enzymes, i.e. they exhibit both lipid kinaseactivity (phosphorylation of phosphoinositides) and protein kinaseactivity, shown to be capable of phosphorylation of protein assubstrate, including autophosphorylation as intramolecular regulatorymechanism. These enzymes of phospholipid signalling are activated byvarious extracellular signals, such as growth factors, mitogens,integrins (cell-cell interactions), hormones, cytokines, viruses, andneurotransmitters, as described in Scheme I below, and also byintracellular regulation by other signaling molecules (cross-talk, wherethe original signal can activate some parallel pathways, which in asecond step transmit signals to PI3Ks by intracellular signalingevents), such as, for example, small GTPases, kinases, or phosphatases.Intracellular regulation can also occur as a result of aberrantexpression or lack of expression of cellular oncogenes or tumoursuppressors. The intracellular inositol phopholipid (phosphoinositide)signaling pathways begin with activation of signaling molecules(extracellular ligands, stimuli, receptor dimerisation, transactivationby a heterologous receptor (for example receptor tyrosine kinase) andwith the recruitment and activation of PI3K, including the involvementof G protein-linked trans-membrane receptor integrated into the plasmamembrane.

PI3K converts the membrane phospholipid PI(4,5)P₂ into PI(3,4,5)P₃,which functions as secondary messenger. PI and PI(4)P are likewisesubstrates of PI3K and can be phosphorylated and converted into PI3P andPI(3,4)P₂, respectively. In addition, these phosphoinositides can beconverted into other phosphoinositides by 5′-specific and 3′-specificphosphatases, meaning that PI3K enzyme activity results either directlyor indirectly in the generation of two 3′-phosphoinositide subtypeswhich function as secondary messengers in intracellular signaltransduction pathways (Trends Biochem. Sci. 22(7) pp. 267-72 (1997) byVanhaesebroeck et al; Chem. Rev. 101(8) pp. 2365-80 (2001) by Leslie etal (2001); Annu. Rev. Cell. Dev. Biol. 17p, 615-75 (2001) by Katso etal. and Cell. Mol. Life Sci. 59(5) pp. 761-79 (2002) by Toker et al.).Multiple PI3K isoforms categorised by their catalytic subunits, theirregulation by corresponding regulatory subunits, expression patterns andsignal-specific functions (p110α, β, δ and γ) perform this enzymereaction (Exp. Cell. Res. 25 (1) pp. 239-54 (1999) by Vanhaesebroeck andKatso et al., 2001, see above).

The closely related isoforms p110α and β are expressed ubiquitously,while δ and γ are expressed more specifically in the haematopoietic cellsystem, in the smooth muscle cells, myocytes and endothelial cells(Trends Biochem. Sci. 22(7) pp. 267-72 (1997) by Vanhaesebroeck et al.).Their expression can also be regulated in an inducible manner dependingon the cellular tissue type and stimuli as well as in accordance withthe particular disease. The inducibility of protein expression includesprotein synthesis as well as protein stabilisation, which is partlyregulated by association with regulatory subunits.

To date, eight mammalian PI3Ks have been identified, divided into 3 mainclasses (I, II and III) on the basis of sequence homology, structure,binding partners, mode of activation, and substrate preference. Invitro, class I PI3Ks are able to phosphorylate phosphatidylinositol(PI), phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol4,5-bisphosphate (PI(4,5)P₂) to give phosphatidylinositol 3-phosphate(PI3P), phosphatidylinositol 3,4-bisphosphate (PI(3,4)P₂, andphosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P₃, respectively.Class II PI3Ks phosphorylate PI and phosphatidylinositol 4-phosphate.Class III PI3Ks can only phosphorylate PI (Vanhaesebroeck et al., 1997,see above; Vanhaesebroeck et al., 1999, see above, and Leslie et al,2001, see above).

As illustrated in Scheme I above, phosphoinositide 3-kinases (PI3Ks)phosphorylate the hydroxyl of the third carbon atom on the inositolring. The phosphorylation of phosphoinositides which converts PtdInsinto 3,4,5-triphosphate (PtdIns(3,4,5)P₃), PtdIns(3,4)P₂ and PtdIns(3)Pproduces secondary messengers for various signal transduction pathways,as are essential, inter alia, for cell proliferation, celldifferentiation, cell growth, cell size, cell survival, apoptosis,adhesion, cell mobility, cell migration, chemotaxis, invasion,cytoskeletal rearrangement, cell shape changes, vesicle trafficking andmetabolic pathway (Katso et al, 2001, see above, and Mol. Med. Today6(9) pp. 347-57 (2000) by Stein). G protein-coupled receptors mediatephosphoinositide 3′-OH kinase activation via small GTPases, such as Gβγand Ras, and consequently PI3K signaling plays a central role in thedevelopment and coordination of cell polarity and dynamic organisationof the cytoskeleton—which together provide the driving force for cellmovement.

Chemotaxis—the directed movement of cells in the direction of aconcentration gradient of chemical attractants, which are also calledchemokines, is also involved in many important diseases, such asinflammation/autoimmunity, neurodegeneration, angiogenesis,invasion/metastasis and wound healing (Immunol. Today 21(6) pp. 260-4(2000) by Wyman et al.; Science 287(5455) pp. 1049-53 (2000) by Hirschet al.; FASEB J. 15(11) pp. 2019-21 (2001) by Hirsch et al., and Nat.Immunol. 2(2) pp. 108-15 (2001) by Gerard et al.).

Advances using genetic approaches and pharmacological tools haveprovided insights into signalling and molecular pathways which promotechemotaxis in response to chemical attractant-activated, Gprotein-coupled sensors. PI3 kinase, which is responsible for thegeneration of these phosphorylated signalling products, was originallyidentified as an activity which is associated with viral oncoproteinsand growth factor tyrosine kinases which phosphorylatephosphatidylinositol (PI) and its phosphorylated derivatives at the3′-hydroxyl of the inositol ring (Panayotou et al., Trends Cell Biol. 2pp. 358-60 (1992)). However, more recent biochemical studies have shownthat class I PI3 kinases (for example class IB isoform PI3Kγ) aredual-specificity kinase enzymes, which means that they exhibit bothlipid kinase activity and protein kinase activity, shown to be capableof phosphorylation of other proteins as substrates, as well asautophosphorylation as an intramolecular regulatory mechanism.

PI3 kinase activation is therefore probably involved in various cellularresponses, including cell growth, differentiation and apoptosis (Parkeret al., Current Biology, 5 pp. 577-99 (1995); Yao et al., Science, 267pp. 2003-05 (1995)). PI3 kinases appear to be involved in a number ofaspects of leukocyte activation. A p85-associated PI3 kinase activityhas been shown to associate physically with the cytoplasmic domain ofCD28, which is an important co-stimulatory molecule for the activationof T cells by antigen (Pages et al., Nature, 369 pp. 327-29 (1994);Rudd, Immunity 4 pp. 527-34 (1996)). Activation of T cells by CD28lowers the threshold for activation by antigen and increases themagnitude and duration of the proliferative response. These effects areaccompanied by increases in the transcription of a number of genes, suchas, inter alia, interleukin-2 (IL2), an important T cell growth factor(Fraser et al., Science 251 pp. 313-16 (1991)). If CD28 is mutated insuch a way that it can no longer interact with PI3 kinase, initiation ofIL-2 production fails, which suggests a crucial role for PI3 kinase in Tcell activation. PI3Kγ has been identified as a promoter ofG-β-γ-dependent regulation of JNK activity, and G-β-γ are subunits ofheterotrimeric G proteins (Lopez-Ilasaca et al, J. Biol. Chem. 273(5)pp. 2505-8 (1998)). Cellular processes in which PI3Ks play an essentialrole include suppression of apoptosis, reorganisation of the actinskeleton, cardiac myocyte growth, glycogen synthase stimulation byinsulin, TNFα-promoted neutrophil priming and superoxide generation, andleukocyte migration and adhesion to endothelial cells.

Laffargue et al., Immunity 16(3) pp. 441-51 (2002), have described thatPI3Kγ relays inflammatory signals via various G(i)-coupled receptors andthat it is crucial for mast cell function, stimuli in connection withleukocytes, and immunology, including cytokines, chemokines, adenosines,antibodies, integrins, aggregation factors, growth factors, viruses orhormones (J. Cell. Sci. 114(Pt 16) pp. 2903-10 (2001) by Lawlor et al.;Laffargue et al., 2002, see above, and Curr. Opinion Cell Biol. 14(2)pp. 203-13 (2002) by Stephens et al.).

Specific inhibitors against individual members of a family of enzymesprovide invaluable tools for deciphering the functions of each enzyme.Two compounds, LY294002 and wortmannin (see below), have been widelyused as PI3 kinase inhibitors. These compounds are non-specific PI3Kinhibitors, since they do not distinguish between the four members ofclass I PI3 kinases. For example, the IC₅₀ values of wortmannin againsteach of the various class I PI3 kinases are in the range from 1 to 10nM. Correspondingly, the IC₅₀ values of LY294002 against each of thesePI3 kinases are about 15 to 20 μM (Fruman et al., Ann. Rev. Biochem.,67, pp. 481-507 (1998)), in addition it has IC₅₀ values of 5-10 μM onCK2 protein kinase and a slight inhibitory activity on phospholipases.Wortmannin is a fungal metabolite which irreversibly inhibits PI3Kactivity by bonding covalently to the catalytic domain of this enzyme.The inhibition of PI3K activity by wortmanin eliminates the subsequentcellular response to the extracellular factor. For example, neutrophilsrespond to the chemokine fMet-Leu-Phe (fMLP) by stimulation of PI3K andsynthesis of PtdIns (3,4,5)P₃. This synthesis correlates with activationof the respiratory burst which is involved in the destruction of theneutrophils of invading microorganisms. Treatment of neutrophils withwortmannin prevents the fMLP-induced respiratory burst response (Thelenet al., Proc. Natl. Acad. Sci. USA, 91, pp. 4960-64 (1994)). Indeed,these experiments with wortmannin, as well as other experimentalevidence, show that PI3K activity in cells of haematopoietic lineage, inparticular neutrophils, monocytes and other types of leukocytes, areinvolved in many of the non-memory immune response associated with acuteand chronic inflammation.

Based on studies with wortmannin, there is evidence that PI3 kinasefunction is also necessary for some aspects of leukocyte signalling by Gprotein-coupled receptors (Thelen et al., 1994, see above). In addition,it has been shown that wortmannin and LY294002 block neutrophilmigration and superoxide release. Carboxygenase-inhibiting benzofuranderivatives are disclosed by John M. Janusz et al., in J. Med. Chem.1998; Vol. 41, No. 18.

It is now well understood that deregulation of oncogenes andtumour-suppressor genes contributes to the formation of malignanttumours, for example by increasing cell growth and proliferation orincreased cell survival. It is now also known that signalling pathwayspromoted by the PI3K family play a central role in a number of cellprocesses, such as, inter alia, in proliferation and survival, andderegulation of these pathways is a causative factor in a broad spectrumof human cancer diseases and other diseases (Katso et al., Annual Rev.Cell Dev. Biol, 2001, 17: 615-617, and Foster et al, J. Cell Science.2003, U6: 3037-3040).

Class I PI3K is a heterodimer consisting of a catalytic p110 subunit anda regulatory subunit, and the family is further divided into class Iaand class Ib enzymes on the basis of the regulatory partners and theregulation mechanisms. Class Ia enzymes consist of three differentcatalytic subunits (p110α, p110β, and p110δ), which dimerise with fivedifferent regulatory subunits (p85α, p55α, p50α, p85β and p55γ), whereall catalytic subunits are able to interact with all regulatory subunitsto form various heterodimers. Class Ia PI3Ks are generally activated inresponse to growth factor stimulation of receptor tyrosine kinases viainteraction of the regulatory SH2 domain subunit with specificphosphotyrosine residues of the activated receptor or adaptor proteins,such as IRS-1. Small GTPases (for example ras) are likewise involved inthe activation of PI3K together with receptor tyrosine kinaseactivation. Both p110α and p110β are constitutively involved in all celltypes, whereas p110δ expression is more restricted to leukocytepopulations and some epithelial cells. By contrast, the only class Ibenzyme consists of a catalytic p110γ subunit, which interacts with aregulatory p101 subunit. In addition, the class Ib enzyme is activatedby G protein-coupled receptor (GPCR) systems, and its expression appearsto be limited to leukocytes.

There is now clear evidence showing that class Ia PI3K enzymescontribute to tumorigenesis in a large number of human cancer diseases,either directly or indirectly (Vivanco and Sawyers, Nature ReviewsCancer, 2002, 2, 489-501). For example, the p110α subunit is amplifiedin some tumours, such as, for example, in ovarian tumours (Shayesteh, etal., Nature Genetics, 1999, 21:99-102) and cervix (Ma et al, Oncogene,2000, 19: 2739-2744). Recently, activating mutations in p110α (PIK3CAgene) have been associated with various other tumours, such as, forexample, colon and breast and lung tumours (Samuels, et al., Science,2004, 304, 554). Tumour-related mutations in p85α have likewise beenidentified in cancer diseases, such as ovarian and colon cancer (Philpet al., Cancer Research, 2001, 61, 7426-7429). Besides direct effects,activation of class I PI3Ks is probably involved in tumorigenic eventsoccurring upstream of signalling pathways, for example by means ofligand-dependent or ligand-independent activation of receptor tyrosinekinases, GPCR systems or integrins (Vara et al., Cancer TreatmentReviews, 2004, 30, 193-204). Examples of such upstream signallingpathways include overexpression of the receptor tyrosine kinase Erb2 ina number of tumours which lead to activation of PI3K-promoted pathways(Harari et al., Oncogene, 2000, Jj), 6102-6114) and overexpression ofthe oncogene Ras (Kauffmann-Zeh et al., Nature, 1997, 385, 544-548). Inaddition, class Ia PI3Ks may contribute indirectly to tumorigenesiscaused by various downstream signalling events. For example, the loss offunction of the PTEN tumour-suppressor phosphatase which catalyses theconversion of PI(3,4,5,)P₃ back to PI(4,5)P₂ is associated with a verybroad range of tumours via deregulation of the PI3K-promoted productionof PI(3,4,5)P₃ (Simpson and Parsons, Exp. Cell Res., 2001, 264, 29-41).In addition, the increase in the effects of other PI3K-promotedsignalling events probably contributes to a number of cancer diseases,for example by activation of AKT (Nicholson and Andeson, CellularSignaling, 2002, 14, 381-395).

Besides a role in the promotion of proliferative and survival signallingin tumour cells, there is good evidence that class I PI3K enzymes alsocontribute to tumorigenesis via their function in tumour-associatedstromal cells. PI3K signalling is known to play an important role in thepromotion of angiogenic events in endothelial cells in response topro-angiogenic factors, such as VEGF (abid et al., Arterioscler. Thromb.Vasc. Biol., 2004, 24, 294-300). Since class I PI3K enzymes are alsoinvolved in mobility and migration (Sawyer, Expert Opinion investing.Drugs, 2004, 13, 1-19), PI3K inhibitors are thought to provide atherapeutic benefit via inhibition of tumour cell invasion andmetastasis.

The synthesis of small compounds which specifically inhibit, regulateand/or modulate PI3 kinase signal transduction is therefore desirableand an aim of the present invention.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

It has been found that the compounds according to the invention areinhibitors of the phosphoinositide 3-kinases (PI3Ks).

The compounds according to the invention inhibit protein kinases, inparticular PI3K, mTOR and DNA-PK. In addition, they activate Foxo3Atranslocation. If the phosphoinositide 3-kinase (PI3K) enzyme isinhibited by a compound according to the invention, PI3K is unable toexert its enzymatic, biological and/or pharmacological effects. Thecompounds according to the invention are therefore suitable for thetreatment of autoimmune diseases, inflammatory diseases, cardiovasculardiseases, neurodegenerative diseases, allergy, asthma, pancreatitis,multiorgan failure, kidney diseases, blood platelet aggregation, cancer,sperm motility, transplant rejection, graft rejection and lung injuries.

The compounds of the formula (I) are suitable, in particular, asmedicaments for the treatment of autoimmune diseases, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, allergy,asthma, pancreatitis, multiorgan failure, kidney diseases, bloodplatelet aggregation, cancer, sperm motility, transplant rejection,graft rejection and lung injuries.

According to an embodiment of the present invention, the compounds ofthe formula (I) are inhibitors of one or more phosphatoinositide3-kinases (PI3Ks), advantageously phosphatoinositide 3-kinase γ (PI3Kγ),phosphatoinositide 3-kinase α (PI3Kα), phosphatoinositide 3-kinase β(PI3Kβ), and/or phosphatoinositide 3-kinase δ (PI3K δ).

The compounds of the formula (I) are suitable for the modulation, inparticular for the inhibition, of the activity of phosphatoinositide3-kinases (PI3Ks), advantageously phosphatoinositide 3-kinase (PI3Kα).The compounds according to the invention are therefore also suitable forthe treatment of disorders which are promoted by PI3Ks. The treatmentincludes the modulation—in particular the inhibition ordownregulation—of phosphatoinositide 3-kinases.

The compounds according to the invention are preferably used for thepreparation of a medicament for the treatment of a disorder selectedfrom multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis,Alzheimer's disease, Huntington's disease, CNS trauma, stroke orischaemic states, cardiovascular diseases, such as atherosclerosis,cardiac hypertrophy, cardiac myocyte dysfunction, hypertension orvasoconstriction.

The compounds of the formula (I) are preferably suitable for thetreatment of autoimmune diseases or inflammatory diseases, such asmultiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis.

The compounds of the formula (I) are preferably suitable for thetreatment of neurodegenerative diseases, such as, inter alia, multiplesclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, strokeor ischaemic states.

The compounds of the formula (I) are preferably suitable for thetreatment of cardiovascular diseases, such as atherosclerosis, cardiachypertrophy, cardiac myocyte dysfunction, hypertension orvasoconstriction.

The compounds of the formula (I) are preferably suitable for thetreatment of chronic obstructive pulmonary disease, anaphylactic shockfibrosis, psoriasis, allergic diseases, asthma, stroke, ischaemicstates, ischemia-reperfusion, blood platelet aggregation or activation,skeletal muscle atrophy or hypertrophy, leukocyte recruitment in cancertissue, angiogenesis, invasion metastasis, in particular melanoma,Karposi's sarcoma, acute and chronic bacterial and viral infections,sepsis, transplant rejection, graft rejection, glomerulosclerosis,glomerulonephritis, progressive renal fibrosis, endothelial andepithelial injuries in the lung, and lung airway inflammation.

Since the pharmaceutically active compounds of the present invention areactive as PI3 kinase inhibitors, in particular the compounds whichinhibit pI3Kα, either selectively or together with one or more of PI3Kδ,PI3Kβ and/or PI3Kγ, they have therapeutic utility in the treatment ofcancer.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected from: brain(gliomas), glioblastomas, leukaemias, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumour, Ewing's sarcoma, rhabdomyosarcoma, ependymoma,medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma,ovary, pancreas, prostate, sarcoma, osteosarcoma, giant-cell tumour ofbone and thyroid.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected from:lymphoblastic T-cell leukaemia, chronic myelogenous leukaemia, chroniclymphocytic leukaemia, hairy-cell leukaemia, acute lymphoblasticleukaemia, acute myelogenous leukaemia, chronic neutrophilic leukaemia,acute lymphoblastic T-cell leukaemia, plasmacytoma, immunoblastic largecell leukaemia, mantle cell leukaemia, multiple myeloma,megakaryoblastic leukaemia, multiple myeloma, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected frommalignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,lymphoblastic T-cell lymphoma, Burkitt's lymphoma and follicularlymphoma. The invention preferably relates to a method for the treatmentof cancer in a mammal, including humans, where the cancer is selectedfrom: neuroblastoma, bladder cancer, urothelial cancer, lung cancer,vulvar cancer, cervical cancer, endometrial cancer, renal cancer,mesothelioma, oesophageal cancer, salivary gland cancer, hepatocellularcancer, bowel cancer, nasopharyngeal cancer, buccal cancer, mouthcancer, GIST (gastrointestinal stromal tumour) and testicular cancer.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of PI3 kinase. Inaddition, they are particularly suitable for use in diagnostic methodsfor diseases in connection with unregulated or disturbed PI3 kinaseactivity.

It can be shown that the compounds according to the invention have anantiproliferative action in vivo in a xenotransplant tumour model. Thecompounds according to the invention are administered to a patienthaving a hyperproliferative disease, for example to inhibit tumourgrowth, to reduce inflammation associated with a lymphoproliferativedisease, to inhibit trans-plant rejection or neurological damage due totissue repair, etc. The present compounds are suitable for prophylacticor therapeutic purposes. As used herein, the term “treatment” is used torefer to both prevention of diseases and treatment of pre-existingconditions. The prevention of proliferation is achieved byadministration of the compounds according to the invention prior to thedevelopment of overt disease, for example to prevent the growth oftumours, prevent metastatic growth, diminish restenosis associated withcardiovascular surgery, etc. Alternatively, the compounds are used forthe treatment of ongoing diseases by stabilising or improving theclinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitmigration, usually between about one hour and one week. In vitro testingcan be carried out using cultivated cells from a biopsy sample. Theviable cells remaining after the treatment are then counted.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. ofBiomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-anti-bodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

PRIOR ART

Other heterocyclic PI3K inhibitors are described in WO 2009/046448 A1,WO 2008/157191 A2 and WO 2008/012326 A1.

Imidazol(on)e derivatives are disclosed in:

WO 2008/094556, WO 2005/105790, WO 2004/026859, WO 2 003/035638 and WO9638421.

Pyrazine derivatives and the use thereof as PI3K inhibitors aredisclosed in WO 2007/023186 A1.Pyridopyrimidines are described in WO 2009/039140 A1 as PI3 kinaseinhibitors.Quinoxaline derivatives are disclosed in WO 2008/127594 as PI3Kinhibitors.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   A¹ denotes N or CR¹,-   A² denotes N or CR²,-   A³, A⁴,-   A⁵, A⁶ each, independently of one another, denote N or CR³,-   X is absent or denotes unbranched or branched alkylene having 1-10 C    atoms, in which 1-7 H atoms may be replaced by OH, F and/or Cl,-    and/or in which one or two non-adjacent CH and/or CH₂ groups may be    replaced by O, N, NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂,    COO, CONH and/or CH═CH groups, or cycloalkylene having 3-7 C atoms,-   L² is absent or denotes unbranched or branched alkylene having 1-10    C atoms, in which 1-7 H atoms may be replaced by OH, F and/or Cl,-    and/or in which one or two non-adjacent CH and/or CH₂ groups may be    replaced by O, N, NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂,    COO, CONH and/or CH═CH groups, or cycloalkylene having 3-7 C atoms,-    with the proviso that X and L² cannot be absent simultaneously,-   R denotes H or unbranched or branched alkyl having 1-10 C atoms, in    which 1-7 H atoms may be replaced by F and/or Cl and/or in which one    or two non-adjacent CH and/or CH₂ groups may be replaced by O, N,    NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/or    CH═CH groups,-    or-    cyclic alkyl having 3-7 C atoms,-   R¹ denotes H or unbranched or branched alkyl having 1-10 C atoms, in    which 1-7 H atoms may be replaced by F and/or Cl and/or in which one    or two non-adjacent CH and/or CH₂ groups may be replaced by O, N,    NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/or    CH═CH groups,-    or-    cyclic alkyl having 3-7 C atoms,-   R² denotes H or unbranched or branched alkyl having 1-10 C atoms, in    which 1-7 H atoms may be replaced by F and/or Cl and/or in which one    or two non-adjacent CH and/or CH₂ groups may be replaced by O, N,    NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/or    CH═CH groups,-   or-    cyclic alkyl having 3-7 C atoms,-   R³ denotes H or unbranched or branched alkyl having 1-10 C atoms, in    which 1-7 H atoms may be replaced by F and/or Cl and/or in which one    or two non-adjacent CH and/or CH₂ groups may be replaced by O, N,    NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/or    CH═CH groups,-    or-    cyclic alkyl having 3-7 C atoms,-   A′ in each case, independently of one another, denotes unbranched or    branched alkyl having 1-10 C atoms,-    in which 1-7 H atoms may be replaced by F and/or Cl,-    and/or in which one or two non-adjacent CH and/or CH₂ groups may be    replaced by O, N, NH, NA, S, SO, SO₂ and/or CH═CH groups,-    or-    cyclic alkyl having 3-7 C atoms,-   A denotes alkyl having 1, 2, 3 or 4 C atoms,    and pharmaceutically usable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios,

Compounds of the formula I are also taken to mean the hydrates andsolvates of these compounds, furthermore pharmaceutically usablederivatives.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. solvates of the compoundsare taken to mean adductions of inert solvent molecules onto thecompounds which form owing to their mutual attractive force. Solvateare, for example, mono- or dihydrates or alcoholates. The inventionnaturally also encompasses the solvates of the salts of the compoundsaccording to the invention. Pharmaceutically usable derivatives aretaken to mean, for example, the salts of the compounds according to theinvention and also so-called prodrug compounds.

Prodrug derivatives are taken to mean compounds of the formula I whichhave been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active compound which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the advance of a disease, complaint or disorder.

The term “therapeutically effective amount” also encompasses the amountswhich are effective for increasing normal physiological function.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically usable salts, tautomers and stereoisomersthereof, characterised in that

a) a compound of the formula II

-   -   in which R, A¹ and A² have the meanings indicated in claim 1, is        reacted with a compound of the formula III

-   -   in which X, L², A³, A4, A⁵ and A⁶ have the meanings indicated in        claim 1,        or        b) a compound of the formula IV

-   -   in which R and A² have the meanings indicated in claim 1 and    -   L denotes a boronic acid or boronic acid ester radical, is        reacted with a compound of the formula V

-   -   in which X, L², A¹, A³, A⁴, A⁵ and A⁶ have the meanings        indicated in claim 1,        and/or        a base or acid of the formula I is converted into one of its        salts.

Above and below, the radicals R, X, L² and A¹-A⁶ have the meaningsindicated in the case of the formula I, unless expressly indicatedotherwise.

A′ denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3,4, 5, 6, 7, 8, 9 or 10 C atoms. A′ preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.

A′ very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

A′ preferably also denotes unbranched or branched alkyl having 1-6 Catoms, in which, in addition, one or two CH₂ groups may be replaced byO. A′ therefore preferably also denotes methoxy, 2-hydroxyethyl or2-methoxyethyl.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3 or4 C atoms.

Cyclic alkyl (cycloalkyl) preferably denotes cyclopropyl, cyclobutyl,cylopentyl, cyclohexyl or cycloheptyl.

X preferably denotes “absent” (a bond) or unbranched or branchedalkylene having 1-4 C atoms (preferably methylene, ethylene, propyleneor butylene), and in which one CH₂ group may be replaced by O, NH, CO orSO₂.

Thus, X denotes, for example, CH₂O, OCH₂, CH₂CO or COCH₂.

L² preferably denotes “absent” (a bond) or unbranched or branchedalkylene having 1-4 C atoms (preferably methylene, ethylene, propyleneor butylene).

R preferably denotes H or unbranched or branched alkyl having 1, 2, 3 or4 C atoms.

R particularly preferably denotes H or methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl.

R¹ preferably denotes H.

R² preferably denotes H.

R³ preferably denotes H or unbranched or branched alkyl having 1, 2, 3or 4 C atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, and in which one CH₂ group may be replaced by O.Thus, R³ preferably also denotes methoxy, 2-hydroxyethyl or2-methoxyethyl.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl. Throughout the invention, all radicals which occur more thanonce may be identical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ii, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia A³, A⁴, A⁵, A⁶ denotes CR³;-   in Ib X is absent or denotes unbranched or branched alkylene having    1-4 C atoms,-    and in which one CH₂ group may be replaced by O, NH, CO or SO₂;-   in Ic L² is absent or denote unbranched or branched alkylene having    1-4 C atoms;-   in Id R denotes H or unbranched or branched alkyl having 1-4 C    atoms;-   in Ie R¹ denotes H;-   in If R² denotes H;-   in Ig R³ denotes H or unbranched or branched alkyl having 1-4 C    atoms and in which one CH₂ group may be replaced by O;-   in 1 h A¹ denotes N or CR¹,    -   A² denotes N or CR²,    -   A³, A⁴, A⁵, A⁶ denote CR³,    -   X is absent or denotes unbranched or branched alkylene having        1-4 C atoms,    -    and in which one CH₂ group may be replaced by O, NH, CO or SO₂,    -   L² is absent or denotes unbranched or branched alkylene having        1-4 C atoms,    -   R denotes H or unbranched or branched alkyl having 1-4 C atoms,    -   R¹ denotes H,    -   R² denotes H,    -   R³ denotes H or unbranched or branched alkyl having 1-4 C atoms        and in which one CH₂ group may be replaced by O;        and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

The starting compounds of the formulae II and III are generally known.If they are novel, however, they can be prepared by methods known perse. Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between 0° and 100°, in particular between about 60° andabout 90°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile and/or DMF.

The reaction is preferably carried out with addition ofbenzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate(BOP) and an organic base, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU).

Compounds of the formula I can furthermore preferably be obtained byreacting a compound of the formula IV with a compound of the formula V.

The reaction is generally carried out under conditions as are known tothe person skilled in the art for a Suzuki reaction.

The starting compounds of the formulae IV and V asre generally known. Ifthey are novel, however, they can be prepared by methods known per se.In the compounds of the formula IV, L preferably denotes

The reaction is carried out under standard conditions of a Suzukicoupling. Depending on the conditions used, the reaction time is betweena few minutes and 14 days, the reaction temperature is between about−30° and 140°, normally between 0° and 100°, in particular between about60° and about 90°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to ethanol, toluene, dimethoxyethane.

The compounds of the formulae I can furthermore be obtained byliberating them from their functional derivatives.

Preferred starting materials are those which contain correspondingprotected amino and/or hydroxyl groups instead of one or more free aminoand/or hydroxyl groups, preferably those which carry an amino-protectinggroup instead of an H atom bonded to an N atom, for example those whichconform to the formula I, but contain an NR′ or NHR′ group (in which R′denotes an amino-protecting group, for example triisopropylsilyl)instead of an NH or NH₂ group.

Silyl protecting groups are preferably cleaved off in the presence offluoride ions under standard conditions.

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, perchloric acid is preferably used in the form ofa mixture of acetic acid and 70% perchloric acid in the ratio 9:1. Thereaction temperatures for the cleavage are advantageously between about0 and about 50°, preferably between 15 and 30° (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can, for example, preferably becleaved off using TFA in dichloromethane or using approximately 3 to 5 NHCl in dioxane at 15-30°, the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

Hydrogenolytically removable protecting groups (for example CBZ orbenzyl) can be cleaved off, for example, by treatment with hydrogen inthe presence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active compound which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active compound compared withthe free form of the active compound or any other salt form of theactive compound used earlier. The pharmaceutically acceptable salt formof the active compound can also provide this active compound for thefirst time with a desired pharmacokinetic property which it did not haveearlier and can even have a positive influence on the pharmacodynamicsof this active compound with respect to its therapeutic efficacy in thebody.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, andoptionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active compound perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of active compoundper dosage unit. Preferred dosage unit formulations are those whichcomprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active compound. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active compound with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units. Oral liquids, such as, for example, solution, syrups andelixirs, can be prepared in the form of dosage units so that a givenquantity comprises a pre-specified amount of the compound. Syrups can beprepared by dissolving the compound in an aqueous solution with asuitable flavour, while elixirs are prepared using a non-toxic alcoholicvehicle. Suspensions can be formulated by dispersion of the compound ina non-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and salts thereof can also beadministered in the form of liposome delivery systems, such as, forexample, small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from variousphospholipids, such as, for example, cholesterol, stearylamine orphosphatidylcholines.

The compounds of the formula I and the salts thereof can also bedelivered using monoclonal antibodies as individual carriers to whichthe compound molecules are coupled. The compounds can also be coupled tosoluble polymers as targeted medicament carriers. Such polymers mayencompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active compoundcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activecompound can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active compound can be formulated to givea cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active compound is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts andstereoisomers thereof, including mixtures thereof in all ratios, and atleast one further medicament active compound.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically usable salts and stereoisomers thereof, including    mixtures thereof in all ratios,-    and-   (b) an effective amount of a further medicament active compound.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically usable salts and stereoisomersthereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active compound indissolved or lyophilised form.

Use

The present compounds are suitable as pharmaceutical active compoundsfor mammals, especially for humans, in the treatment of diseases.

The present invention encompasses the compounds of the formula I for usein the treatment or prevention of autoimmune diseases, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases, allergy,asthma, pancreatitis, multiorgan failure, kidney diseases, bloodplatelet aggregation, cancer, sperm motility, transplant rejection,graft rejection and lung injuries.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofautoimmune diseases, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, allergy, asthma, pancreatitis, multiorganfailure, kidney diseases, blood platelet aggregation, cancer, spermmotility, transplant rejection, graft rejection and lung injuries.

The compounds according to the invention are preferably used for thepreparation of a medicament for the treatment of a disorder selectedfrom multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis,Alzheimer's disease, Huntington's disease, CNS trauma, stroke, orischaemic states, cardiovascular diseases, such as atherosclerosis,cardiac hypertrophy, cardiac myocyte dysfunction, hypertension orvasoconstriction.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofautoimmune diseases or inflammatory diseases, such as multiplesclerosis, psoriasis, rheumatoid arthritis, systemic lupuserythematosus, inflammatory bowel disease, lung inflammation, thrombosisor brain infection or inflammation, such as meningitis or encephalitis.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofneurodegenerative diseases, such as, inter alia, multiple sclerosis,Alzheimer's disease, Huntington's disease, CNS trauma, stroke orischaemic states.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention ofcardiovascular diseases, such as atherosclerosis, cardiac hypertrophy,cardiac myocyte dysfunction, hypertension or vasoconstriction.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of chronicobstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis,allergic diseases, asthma, stroke, ischaemic states,ischemia-reperfusion, blood platelet aggregation or activation, skeletalmuscle atrophy or hypertrophy, leukocyte recruitment in cancer tissue,angiogenesis, invasion metastasis, in particular melanoma, Karposi'ssarcoma, acute and chronic bacterial and viral infections, sepsis,transplant rejection, graft rejection, glomerulosclerosis,glomerulonephritis, progressive renal fibrosis, endothelial andepithelial injuries in the lung, and lung airway inflammation.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of cancer ina mammal, including humans, where the cancer is selected from: brain(gliomas), glioblastomas, leukaemias, Bannayan-Zonana syndrome, Cowdendisease, Lhermitte-Duclos disease, breast cancer, inflammatory breastcancer, Wilm's tumour, Ewing's sarcoma, rhabdomyosarcoma, ependymoma,medulloblastoma, colon, head and neck, kidney, lung, liver, melanoma,ovary, pancreas, prostate, sarcoma, osteosarcoma, giant-cell tumour ofbone and thyroid.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of cancer ina mammal, including humans, where the cancer is selected from:lymphoblastic T-cell leukaemia, chronic myelogenous leukaemia, chroniclymphocytic leukaemia, hairy-cell leukaemia, acute lymphoblasticleukaemia, acute myelogenous leukaemia, chronic neutrophilic leukaemia,acute lymphoblastic T-cell leukaemia, plasmacytoma, immunoblastic largecell leukaemia, mantle cell leukaemia, multiple myeloma,megakaryoblastic leukaemia, multiple myeloma, acute megakaryocyticleukaemia, promyelocytic leukaemia and erythroleukaemia.

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts thereof for thepreparation of a medicament for the treatment or prevention of cancer ina mammal, including humans, where the cancer is selected from malignantlymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblasticT-cell lymphoma, Burkitt's lymphoma and follicular lymphoma.

The invention preferably relates to a method for the treatment of cancerin a mammal, including humans, where the cancer is selected from:neuro-blastoma, bladder cancer, urothelial cancer, lung cancer, vulvarcancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma,oesophageal cancer, salivary gland cancer, hepatocellular cancer, bowelcancer, nasopharyngeal cancer, buccal cancer, mouth cancer, GIST(gastro-intestinal stromal tumour) and testicular cancer.

The compounds of the formula I can furthermore be used in order topro-vide additive or synergistic effects in certain existing cancerchemotherapies, and/or can be used in order to restore the efficacy ofcertain existing cancer chemotherapies and radiotherapies.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts thereof for the preparation of amedicament in a mammal, where a therapeutically effective amount of acompound according to the invention is administered. The therapeuticamount varies according to the specific disease and can be determined bythe person skilled in the art without undue effort.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:

(i) antiproliferative/antineoplastic/DNA-damaging agents andcombinations thereof, as used in medical oncology, such as alkylatingagents (for example cis-platin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chloroambucil, busulphan and nitrosoureas);antimetabolites (for example antifolates such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinoside, hydroxyurea and gemcitabine); antitumour antibiotics (forexample anthracyclines, like adriamycin, bleomycin, doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin andmithramycin); antimitotic agents (for example vincan alkaloids, likevincristine, vinblastine, vindesine and vinorelbine, and taxoids, liketaxol and taxotere); topoisomerase inhibitors (for exampleepipodophyllotoxins, like etoposide and teniposide, amsacrine,topotecan, irinotecan and camptothecin) and cell-differentiating agents(for example all-trans-retinoic acid, 13-cis-retinoic acid andfenretinide);(ii) cytostatic agents, such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordownregulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progesterones (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase, such as finasteride;(iii) agents which inhibit cancer cell invasion (for examplemetallo-proteinase inhibitors, like marimastat, and inhibitors ofurokinase plasminogen activator receptor function);(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbbl antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors, such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino-propoxy)quinazolin-4-amine(Cl 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;(v) antiangiogenic agents, such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in published international patentapplications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) andcompounds that work by other mechanisms (for example linomide,inhibitors of integrin αvβ3 function and angiostatin);(vi) vessel-damaging agents, such as combretastatin A4 and compoundsdisclosed in international patent applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-Ras antisense;(viii) gene therapy approaches, including, for example, approaches forreplacement of aberrant genes, such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches, such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme, and approaches for increasing patient toleranceto chemotherapy or radiotherapy, such as multi-drug resistance genetherapy; and(ix) immunotherapy approaches, including, for example, ex-vivo andin-vivo approaches for increasing the immunogenicity of patient tumourcells, such as transfection with cytokines, such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches for decreasing T-cell anergy, approaches using transfectedimmune cells, such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines, and approaches usinganti-idiotypic antibodies.

The medicaments from Table 1 below are preferably, but not exclusively,combined with the compounds of the formula I.

TABLE 1 Alkylating agents Cyclophosphamide Lomustine BusulfanProcarbazine Ifosfamide Altretamine Melphalan Estramustine phosphateHexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucilTemozolomide Dacarbazine Semustine Carmustine Platinum agents CisplatinCarboplatin Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin(Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Matthey)Tetraplatin BBR-3464 (Hoffrnann- Ormiplatin La Roche) IproplatinSM-11355 (Sumitomo) AP-5280 (Access) Antimetabolites Azacytidine TomudexGemcitabine Trimetrexate Capecitabine Deoxycoformycin 5-fluorouracilFludarabine Floxuridine Pentostatin 2-chlorodesoxyadenosine Raltitrexed6-Mercaptopurine Hydroxyurea 6-Thioguanine Decitabine (SuperGen)Cytarabine Clofarabine (Bioenvision) 2-fluorodesoxycytidine Irofulven(MGI Pharrna) Methotrexate DMDC (Hoffmann-La Roche) IdatrexateEthynylcytidine (Taiho) Topoisomerase Amsacrine Rubitecan (SuperGen)inhibitors Epirubicin Exatecan mesylate (Daiichi) Etoposide Quinamed(ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma-Tau) Irinotecan(CPT-11) Diflomotecan (Beaufour- 7-Ethyl-10-hydroxy- Ipsen) camptothecinTAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet(TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350(BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis)KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna) Antitumour antibioticsDactinomycin (Actinomycin D) Amonafide Doxorubicin (Adriamycin)Azonafide Deoxyrubicin Anthrapyrazole Valrubicin OxantrazoleDaunorubicin (Daunomycin) Losoxantrone Epirubicin Bleomycin sulfate(Blenoxan) Therarubicin Bleomycinic acid Idarubicin Bleomycin ARubidazon Bleomycin B Plicamycinp Mitomycin C Porfiromycin MEN-10755(Menarini) Cyanomorpholinodoxorubicin GPX-100 (Gem Mitoxantron(Novantron) Pharmaceuticals) Antimitotic agents Paclitaxel SB 408075(GlaxoSmithKline) Docetaxel E7010 (Abbott) Colchicine PG-TXL (CellTherapeutics) Vinblastine IDN 5109 (Bayer) Vincristine A 105972 (Abbott)Vinorelbine A 204197 (Abbott) Vindesine LU 223651 (BASF) Dolastatin 10(NCI) D 24851 (ASTA Medica) Rhizoxin (Fujisawa) ER-86526 (Eisai)Mivobulin (Warner-Lambert) Combretastatin A4 (BMS) Cemadotin (BASF)Isohomohalichondrin-B RPR 109881A (Aventis) (PharmaMar) TXD 258(Aventis) ZD 6126 (AstraZeneca) Epothilone B (Novartis) PEG-Paclitaxel(Enzon) T 900607 (Tularik) AZ10992 (Asahi) T 138067 (Tularik) !DN-5109(Indena) Cryptophycin 52 (Eli Lilly) AVLB (Prescient Vinflunine (Fabre)NeuroPharma) Auristatin PE (Teikoku Azaepothilon B (BMS) Hormone)BNP-7787 (BioNumerik) BMS 247550 (BMS) CA-4-prodrug (OXiGENE) BMS 184476(BMS) Dolastatin-10 (NrH) BMS 188797 (BMS) CA-4 (OXiGENE) Taxoprexin(Protarga) Aromatase Aminoglutethimide Exemestan inhibitors LetrozoleAtamestan (BioMedicines) Anastrazole YM-511 (Yamanouchi) FormestanThymidylate synthase Pemetrexed (Eli Lilly) Nolatrexed (Eximias)inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonistsTrabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (BaxterInternational) International) Apaziquone (Spectrum Albumin + 32P(Isotope Pharmaceuticals) Solutions) O6-benzylguanine (Paligent)Thymectacin (NewBiotics) Edotreotid (Novartis) Farnesyl transferaseArglabin (NuOncology Labs) Tipifarnib (Johnson & inhibitors lonafarnib(Schering-Plough) Johnson) BAY-43-9006 (Bayer) Perillyl alcohol (DORBioPharma) Pump inhibitors CBT-1 (CBA Pharma) Zosuquidartrihydrochloride Tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG)Biricodar dicitrate (Vertex) Histone Tacedinaline (Pfizer)Pivaloyloxymethyl butyrate acetyl-transferase SAHA (Aton Pharma) (Titan)inhibitors MS-275 (Schering AG) Depsipeptide (Fujisawa)Metalloproteinase Neovastat (Aeterna Laboratorie CMT-3 (CollaGenex)inhibitors Marimastat (British Biotech) BMS-275291 (Celltech)Ribonucleoside Gallium maltolate (Titan) Tezacitabine (Aventis)reductase Triapin (Vion) Didox (Molecules for Health) inhibitorsTNF-alpha Virulizin (Lorus Therapeutics) Revimid (Celgene)agonists/antagonists CDC-394 (Celgene) Endothelin-A Atrasentan (Abbot)YM-598 (Yamanouchi) receptor antagonists ZD-4054 (AstraZeneca) Retinoicacid Fenretinide (Johnson & Alitretinoin (Ligand) receptor agonistsJohnson) LGD-1550 (Ligand) Immunomodulators Interferon Dexosome therapy(Anosys) Oncophage (Antigenics) Pentrix (Australian Cancer GMK(Progenics) Technology) Adenocarcinoma vaccine JSF-154 (Tragen)(Biomira) Cancer vaccine (Intercell) CTP-37 (AVI BioPharma) Norelin(Biostar) JRX-2 (Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech)MGV (Progenics) Synchrovax vaccines (CTL !3-Alethin (Dovetail) Immuno)CLL-Thera (Vasogen) Melanoma vaccine (CTL Immuno) p21-RAS vaccine(GemVax) Hormonal and Oestrogens Prednisone antihormonal agentsConjugated oestrogens Methylprednisolone Ethynyloestradiol Prednisolonechlorotrianisene Aminoglutethimide Idenestrol LeuprolideHydroxyprogesterone caproate Goserelin Medroxyprogesterone LeuporelinTestosterone Bicalutamide Testosterone propionate FlutamideFluoxymesterone Octreotide Methyltestosterone NilutamideDiethylstilbestrol Mitotan Megestrol P-04 (Novogen) Tamoxifen2-Methoxyoestradiol Toremofin (EntreMed) Dexamethasone Arzoxifen (EliLilly) Photodynamic Talaporfin (Light Sciences) Pd-bacteriopheophorbideagents Theralux (Theratechnologies) (Yeda) Motexafin-GadoliniumLutetium-Texaphyrin (Pharmacyclics) (Pharmacyclics) Hypericin Tyrosinekinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen/Pharmacia CEP-701 (Cephalon) ZDI839 (AstraZeneca) CEP-751(Cephalon) Erlotinib (Oncogene Science) MLN518 (Millenium) Canertjnib(Pfizer) PKC412 (Novartis) Squalamine (Genaera) Phenoxodiol O SU5416(Pharmacia) Trastuzumab (Genentech) SU6668 (Pharmacia) C225 (ImClone)ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210(Medarex) Vatalanib (Novartis) 2C4 (Genentech) PKI166 (Novartis) MDX-447(Medarex) GW2016 (GlaxoSmithKline) ABX-EGF (Abgenix) EKB-509 (Wyeth)IMC-1C11 (ImClone) EKB-569 (Wyeth) Various agents SR-27897 (CCK-Ainhibitor, BCX-1777 (PNP inhibitor, Sanofi-Synthelabo) BioCryst)Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist, Ribapharm)stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNAsynthesis Aventis) inhibitor, Dong-A) CV-247 (COX-2 inhibitor, IvyTirapazamine (reducing Medical) agent, SRI International) P54 (COX-2inhibitor, N-Acetylcysta Phytopharm) (reducing agent, Zambon) CapCell ™(CYP450 stimulant, R-Flurbiprofen (NF-kappaB Bavarian Nordic) inhibitor,Encore) GCS-IOO (gal3 antagonist, 3CPA (NF-kappaB inhibitor,GlycoGenesys) Active Biotech) G17DT immunogen (gastrin Seocalcitol(vitamin D inhibitor, Aphton) receptor agonist, Leo) Efaproxiral(oxygenator, Allos 131-I-TM-601 (DNA Therapeutics) antagonist,TransMolecular) PI-88 (heparanase inhibitor, Eflornithin (ODC inhibitor,Progen) ILEX Oncology) Tesmilifen (histamine Minodronic acid (osteoclastantagonist, YM BioSciences) inhibitor, Yamanouchi) Histamine (histamineH2 Indisulam (p53 stimulant, receptor agonist, Maxim) Eisai) Tiazofurin(IMPDH inhibitor, Aplidine (PPT inhibitor, Ribapharm) PharmaMar)Cilengitide (integrin antagonist, Rituximab (CD20 antibody, Merck KGaA)Genentech) SR-31747 (IL-1 antagonist, Gemtuzumab (CD33Sanofi-Synthelabo) antibody, Wyeth Ayerst) CCI-779 (mTOR kinase PG2(haematopoiesis inhibitor, Wyeth) promoter, Pharmagenesis) Exisulind(PDE-V inhibitor, Immunol ™ (triclosan Cell Pathways) mouthwash, Endo)CP-461 (PDE-V inhibitor, Cell Triacetyluridine (uridine Pathways)prodrug, Wellstat) AG-2037 (GART inhibitor, SN-4071 (sarcoma agent,Pfizer) Signature BioScience) WX-UK1 (plasminogen TransMID-107 ™activator inhibitor, Wilex) (immunotoxin, KS Biomedix) PBI-1402 (PMNstimulant, PCK-3145 (apoptosis ProMetic LifeSciences) promoter, Procyon)Bortezomib (proteasome Doranidazole (apoptosis inhibitor, Millennium)promoter, Pola) SRL-172 (T-cell stimulant, CHS-828 (cytotoxic SR Pharma)agent, Leo) TLK-286 (glutathione-S trans-Retinoic acid transferaseinhibitor, Telik) (differentiator, NIH) PT-100 (growth factor MX6(apoptosis promoter, agonist, Point Therapeutics) MAXIA) Midostaurin(PKC inhibitor, Apomine (apoptosis promoter, Novartis) ILEX Oncology)Bryostatin-1 (PKC stimulant, Urocidine (apoptosis promoter, GPC Biotech)Bioniche) CDA-II (apoptosis promoter, Ro-31-7453 (apoptosis Everlife)promoter, La Roche) SDX-101 (apoptosis promoter, Brostallicin (apoptosisSalmedix) promoter, Pharmacia) Ceflatonin (apoptosis promoter,ChemGenex)

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

Assays

The compounds of the formula I described in the examples were tested inthe assays described below, and it was found that they have akinase-inhibiting activity. Other assays are known from the literatureand could readily be performed by the person skilled in the art (see,for example, Dhana-bal et al., Cancer Res. 59:189-197; Xin et al., J.Biol. Chem. 274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441;Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. CancerInst. 52:413-427; Nicosia et al., In Vitro 18:538-549).

Description of the Method for the Cellular Testing of PI3K Inhibitors

The measure used for the cellular PI3K activity is the PI3K-dependentphosphorylation of PKB at Serin 473. The cellular assay fordetermination of the P-S473-PKB level is carried out as a Luminex assayin 96-well format in PC3 cells. PC3 cells exhibit constitutivephosphorylation of PKB owing to a PTEN mutation.

PC3 cells are sown out with 20,000 cells per well in 100 μl medium (45%RPMI1460/45% Ham's F12/10% FCS) and incubated on the following day for30 min with a serial dilution of the test substance (7 concentrations)under serum-free conditions. The cells are subsequently lysed using 90μl of lysis buffer (20 mM Tris/HCl pH 8.0, 150 mM NaCl, 1% NP40, 10%glycerol, 1% phosphatase inhibitor I, 1% phosphatase inhibitor II, 0.1%protease inhibitor cocktail III, 0.01% benzonase) per well, and thelysates are separated off from insoluble cell constituents by means ofcentrifugation through a 96-well filter plate (0.65 μm). The lysates areincubated overnight at 4° C. with shaking with Luminex beads to which ananti-total PKB antibody is coupled. The detection is carried out on thefollowing day by addition of a P-S473-PKB antibody and aspecies-specific PE-labelled secondary antibody. The detection ofP-S473-PKB is carried out by measurement in a Luminex100 instrument bydetermination of 100 events per cavity in a measurement time of 60 sec.As pharmacological blank, the signals obtained from cells which havebeen treated with 3 μM wortmannin are subtracted from all otherpreparations. The control value used for maximum phosphorylation of PKBat S473 are the signals from cells which have been treated only with thesolvent (0.3% DMSO). The values of the preparations treated with testsubstance are calculated from this as percent of control, and IC50values are determined by means of RS1.

Description of the Method for the Testing of DNA-PK Inhibitors

The kinase assay is carried out in 348-well microtitre FlashPlates®,coated with streptavidin. 1.5 μg of the DNA-PK protein complex and 100mg of biotinylated substrate, for example PESQEAFADLWKK biotin-NH2(“biotin-DNA-PK peptide”) in a total volume of 36.5 μl (34.25 mMHepes/KOH, 7.85 mM Tris-HCl, 68.5 mM KCl, 5 μM ATP, 6.85 mM MgCl2, 0.5mM EDTA, 0.14 mM EGTA, 0.69 mM DTT, pH 7.4), are incubated at roomtemperature for 90 minutes with or without test substance in a wellcontaining 500 ng of DNA from calf thymus, 0.1 μCi of 33P-ATP and 1.8%of DMSO. The reaction is stopped by addition of 50 μl/well of 200 mMEDTA. After incubation for 30 minutes, the liquids are removed at roomtemperature. Each well is washed three times with 100 μl of 0.9% NaClsolution. Non-specific reaction (blank) is determined using aproprietary kinase inhibitor (10 μM). The radioactivity is measured bymeans of a Topcount. IC50 values calculated in RS1. Literature:Molecular Cancer Therapeutics 2003, 1257-1264; DNA-dependent proteinkinase inhibitors as drug candidates for the treatment of cancer; A.Kashishian, H. Douangpanya, D. Clark, S. T. Schlachter, C. Todd Eary, J.G. Schiro, H. Huang, L. E. Burgess, E. A. Kesicki, and J. Halbrook.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate, evaporated and purified by chromatographyon silica gel and/or by crystallisation. Rf values on silica gel;eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺

APCI-MS (atmospheric pressure chemical ionisation-mass spectrometry)(M+H)⁺.

Abbreviations:

M—mol/l

min.—minute(s)

h—hour(s)

THF—tetrahydrofuran

Me—methyl

MTBE—tert-butyl methyl ether

DMF—N,N-dimethylformamide

EtOAc—ethyl acetate

HOAc—acetic acid

PE—petroleum ether

Et₂O—diethyl ether

NBS—N-bromosuccinimide

MeOH—methanol

EtOH—ethanol

TFA—trifluoroacetic acid

Tf—triflate (—SO₂—CF₃)

TMS—trimethylsilyl

conc. HCl—concentrated hydrochloric acid

Cy—cyclohexyl

General Experimental Conditions:

All work with air- or moisture-sensitive substances is carried out underan argon or nitrogen atmosphere. All commercially available reagents andsolvents are employed without further purification, unless indicatedotherwise.

Thin-Layer Chromatography (TLC):

Merck silica gel 60 F-254 TLC plates (glass or aluminium). The detectionis carried out in the UV, using I₂ and/or using 5% ethanolicphosphmolybdate solution with subsequent heating by means of a hot-airfan.

Column chromatography:

Stationary phase Merck silica gel 60, 63-200 μm or Merck silica gel 60,40-63 μm.

Microwave (MW):

Emrys™ Optimiser EXP from Personal Chemistry

Melting Points (m.p.):

The melting-point determination is carried out by means of a BüchiB-5459 melting point apparatus. All melting points indi-cated areuncorrected.

Nuclear Resonance Spectroscopy (NMR):

¹H- and ¹³C-NMR spectra are recorded on 300, 400 and 500 MHz NMRinstruments from Bruker. The chemical shifts δ are indicated in ppm, thecoupling constants in Hz.

RP-HPLC with UV and MS Detection (LC-MS):

t_(R)—retention time; TIC—total ion count, [MH]⁺ as m/e values;instrument—Aglient 1100 series (DAD and MS detector) with Sedex 75 ELSdetector from ERC; ion source—electrospray (positive mode);scan—100-1000 m/e; fragmentation voltage—60 V; gas temperature—300° C.;DAD—220 nm; flow rate—2.4 ml/min, a splitter reduces the flow rate afterthe DAD for MS detection to 0.75 ml/min.; column—Chromolith Speed RODRP-18e 50-4.6; solvent—LiChrosolv (Merck KGaA); mobile phase A—H₂O(0.01% TFA); mobile phase B—acetonitrile (0.01% TFA); gradient—from 96%A to 100% B in 2.6 min; then 100% B for 0.7 min.

HPLC Conditions N:

N:gradient: 5.5 min; flow rate.: 2.75 ml/min from

90:10 to −0:100 H₂O/ACN

Water+TFA (0.01% vol.); acetonitrile+TFA(0.01% vol.)

Column: Chromolith SpeedROD RP 18e 50-4.6 Wavelength: 220 nm LCMS PolarMethod:

Agilent 1200 series instrument

Column: Chromolith Speed Rod RP 18e 50-4.6 mm

LCMS polar.m, 2.4 ml/min, 220 nm, buffer A 0.05% of HCOOH/H₂O, buffer B0.04% of HCOOH/acetonitrile, 0.0-3.0 min 5%-100% of B, 3.0-3.5 minbuffer B.Synthesis sequence 1: (“A1”, “A2”, “A3”)

Synthesis sequence 2: (“A4”, “A5”, “A11”, “A12”, “A13”)

Synthesis sequence 3: (“A6”, “A7”)

Synthesis sequence 4: (“A8”, “A9”)

Synthesis sequence 5: (“A10”)

EXAMPLE 1 Preparation of4-(2,3-dihydroindol-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline(“A1”) 1.1 Preparation of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine

3.00 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridineare suspended in 40 ml of tetrahydrofuran in a flask. 0.73 g of sodiumhydride (60% in paraffin oil) are added in portions with ice-cooling.3.94 ml of chlorotriisopropylsilane is subsequently added dropwise atabout 25° C., and the mixture is heated at 40° C. (bath temperature)under nitrogen until the boronic acid ester has reacted completely (HPLCcheck, about 5 hours). The excess sodium hydride is deactivated using 10ml of saturated sodium chloride solution. The solvent is removed invacuo. The residue is diluted with about 50 ml of water and extractedthree times with diethyl ether. The combined organic phases are driedover sodium sulfate and purified by means of column chromatography(gradient heptane: EA 5-100% in 15 min.), giving 4.55 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridineas white solid (yield 92%, content 92%); MS-FAB (M+H⁺)=401.2; R_(f)(nonpolar method): 3.61 min.

1.2 Preparation of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline

0.60 g of 4-chloro-6-iodoquinazoline, 0.31 ml of 2,3-dihydro-1H-indoleand 0.50 ml of triethylamine in 5.00 ml of dioxane are heated at 80° C.in a flask until the quinazoline has reacted completely (HPLC check,about 24 hours). The cooled reaction solution is evaporated to drynessin a rotary evaporator. The residue is purified by means of columnchromatography (gradient EA: methanol 0-20% in 16 min.), giving 0.60 gof 4-(2,3-dihydroindol-1-yl)-6-iodo-quinazoline as yellowish solid(yield 85%, content 97%); MS-FAB (M+H⁺)=373.8; R_(f) (polar method):2.21 min.

1.3 Preparation of4-(2,3-dihydroindol-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo-[2,3-b]pyridin-5-yl)quinazoline

0.20 g of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline, 0.21 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine,0.13 g of sodium hydrogencarbonate and 0.07 g of Pd(PPh₃)₂Cl₂ in 5.00 mlof dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 5 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography; (gradient heptane: EA 5-100% in 16 min),giving 0.20 g of4-(2,3-dihydroindol-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazolineas white powder (yield 71%, content 99%); EI-MS (M+H⁺)=519.2.

1.4 Preparation of4-(2,3-dihydroindol-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline(“A1”)

0.19 g of4-(2,3-dihydroindol-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)quinazolineand 0.08 g of caesium fluoride in 1 ml of acetonitrile are stirred at25° C. in a flask until the reaction is complete (HPLC check, about 24hours). A precipitate precipitates out of the reaction solution. This isfiltered off, rinsed with water and dried, giving 0.04 g of4-(2,3-dihydroindol-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolineas white solid (yield 31%, content 97%); MS-FAB (M+H⁺)=363.9; R_(f)(polar method): 1.71 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.76 (s, 1H), 8.74 (s, 1H), 8.58 (d,J=2.1, 1H), 8.32 (dd, J=13.7, 1.9, 2H), 8.27 (dd, J=8.7, 1.9, 1H), 7.98(d, J=8.7, 1H), 7.54 (d, J=3.2, 1H), 7.49 (d, J=8.0, 1H), 7.35 (d,J=7.2, 1H), 7.17 (t, J=7.6, 1H), 7.01 (t, J=7.3, 1H), 6.52 (d, J=3.3,1H), 4.56 (t, J=8.0, 2H), 3.22 (t, J=7.9, 2H).

EXAMPLE 2 Preparation of4-(1,3-dihydroisoindol-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline(“A2”) 2.1 Preparation of 4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline

0.50 g of 4-chloro-6-iodoquinazoline, 0.27 g of2,3-dihydro-1H-isoindole, 0.42 ml of triethylamine in 4 ml of dioxaneare heated at 80° C. in a flask until the quinazoline has reactedvirtually completely (HPLC check, about 3 hours). The cooled reactionsolution is evaporated to dryness in a rotary evaporator. The residue issuspended in EA. The undissolved solid is filtered off, rinsed withwater and dried, giving 0.56 g of4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline as slightly yellowishsolid (yield 93%, content 94%); MS-FAB (M+H⁺)=373.8; R_(f) (polarmethod): 1.73 min. This is employed for the next step without furtherpurification.

2.2 Preparation of4-(1,3-dihydroisoindol-2-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline

0.25 g of 4-(1,3-dihydroisoindol-2-yl)-6-iodoquinazoline, 0.32 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]-pyridine,0.16 g of sodium hydrogencarbonate and 0.09 g of PdCl₂(PPh₃)₂ in 5.00 mlof dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in aflask until the iodide has reacted completely (HPLC check, about 8hours). The cooled reaction solution is diluted with EA and washed 3times with water. The organic phase is dried over sodium sulfate andpurified by means of column chromatography (gradient heptane: EA 5-100%in 30 min), giving 0.12 g of4-(1,3-dihydroisoindol-2-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolineas slightly beige solid (yield 33%, content 95%); MS-FAB (M+H⁺)=520.0;R_(f) (polar method): 2.77 min.

2.3 Preparation of4-(1,3-dihydroisoindol-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline

0.12 g of4-(1,3-dihydroisoindol-2-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]-pyridin-5-yl)quinazolineand 0.05 g of caesium fluoride in 1 ml of acetonitrile are stirred at25° C. in a flask until the reaction is complete (HPLC check about 24hours). A precipitate precipitates out of the reaction solution. This isfiltered off, rinsed with water and dried, giving 0.08 g of4-(1,3-dihydroisoindol-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline(“A2”) as white solid (yield 95%, content 96%); MS-FAB (M+H⁺)=363.8;R_(f) (polar method): 1.63 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.76 (s, 1H), 8.72 (d, J=2.2, 2H),8.56 (s, 1H), 8.41 (d, J=2.0, 1H), 8.17 (dd, J=8.6, 1.8, 1H), 7.87 (d,J=8.6, 1H), 7.57-7.54 (m, 1H), 7.51 (dd, J=5.4, 3.2, 2H), 7.36 (dd,J=5.6, 3.1, 2H), 6.57 (dd, J=3.4, 1.8, 1H), 5.48 (d, J=33.1, 2H), 1.04(d, J=2.6, 2H).

EXAMPLE 3 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline(“A3”) 3.1 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo-[2,3-b]pyridin-5-yl)quinazoline

0.50 g of 4-chloro-6-iodoquinazoline, 0.30 g of1,2,3,4-tetrahydroquinoline and 0.40 ml of triethylamine in 4 ml ofdioxane are heated at 80° C. in a flask until the quinazoline hasreacted completely (HPLC check, about 24 hours). The cooled reactionsolution is evaporated to dryness in a rotary evaporator. The residue ispurified by means of column chromatography (gradient heptane: EA 5-100%in 16 min.), giving 0.27 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolineas yellow solid (yield 43%, content 96%); MS-FAB (M+H⁺)=387.8; R_(f)(polar method): 2.43 min.

3.2 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1-triisopropyl-silanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline

0.25 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline,0.31 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine,0.16 g of sodium hydrogen-carbonate and 90 mg of PdCl₂(PPh₃)₂ in 5.00 mlof dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 18 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient heptane: EA 5-100% in 16 min),giving 0.20 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazolineas yellow oil (yield 50%, content 83%).

This is employed for the next step without further purification.

3.3 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo-[2,3-b]pyridin-5-yl)quinazoline

0.20 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolineand 0.08 g of caesium fluoride in 1 ml of acetonitrile and 1 ml ofdichloromethane are stirred at 25° C. in a flask until the reaction iscomplete (HPLC check, about 24 hours). A precipitate precipitates out ofthe reaction solution. This is filtered off, rinsed with water anddried, giving 0.02 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline(“A3”) as white solid (yield 13%, content 95%); MS-FAB (M+H⁺)=377.9;R_(f) (polar method): 1.79 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.70 (s, 1H), 8.85 (s, 1H), 8.15 (dd,J=8.7, 2.0, 1H), 8.11 (d, J=2.1, 1H), 7.94 (d, J=8.7, 1H), 7.87 (d,J=2.0, 1H), 7.58 (d, J=1.9, 1H), 7.54-7.48 (m, 1H), 7.35 (d, J=7.0, 1H),7.14 (t, J=7.0, 1H), 7.07 (t, J=7.5, 1H), 6.77 (d, J=7.9, 1H), 6.44 (dd,J=3.3, 1.8, 1H), 4.05 (t, J=6.5, 2H), 2.89 (t, J=6.5, 2H), 2.12-2.00 (m,2H).

EXAMPLE 4 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine(“A6”) 4.1 Preparation of methyl 3-amino-6-bromopyridine-2-carboxylate

20 g of methyl 3-aminopyridine-2-carboxylate are suspended in 120 ml ofwater in a flask. After addition of 100 ml of sulfuric acid (2 mol/l),the mixture is cooled to 0° C., 6.73 ml of bromine are added dropwise,and the mixture is stirred at 25° C. until the acid has reactedcompletely (HPLC check, about 24 hours). A precipitate precipitates outof the reaction solution. This is filtered off, dissolved in EA, washedwith sodium thiosulfate solution, the organic phase is dried andpurified by means of column chromatography (gradient heptane: EA 5-100%in 30 min.), giving 15 g of methyl3-amino-6-bromo-pyridine-2-carboxylate as red-brown solid (yield 50%,content 98%); MS-FAB (M+H⁺)=232.9; R_(f) (polar method): 1.518 min.

4.2 Preparation of methyl3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo-[2,3-b]pyridin-5-yl)pyridine-2-carboxylate

7.50 g of methyl 3-amino-6-bromopyridine-2-carboxylate, 12.10 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo-[2,3-b]pyridine,8.18 g of sodium hydrogencarbonate and 2.27 g of PdCl₂(PPh₃)₂ in 90 mlof dioxane and 15 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 7 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient heptane: EA 5-100% in 25 min),giving 8.40 g of methyl3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxylateas white solid (yield 56%, content 92%); MS-FAB (M+H⁺)=425.2; R_(f)(Esi1rod method): 3.10 min.

4.3 Preparation of6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]-pyrimidin-4-one

3.80 g of methyl3-amino-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylatein 60 ml of formamide are heated at 120° C. under nitrogen in a flaskuntil the reaction is complete (HPLC check, about 52 hours). The cooledreaction solution is added to about 50 ml of water, during which aprecipitate precipitates out. This is filtered off with suction anddried, giving 2.00 g of6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one asorange solid (yield 83%, content 98%); MS-FAB (M+H⁺)=264.1; R_(f) (polarmethod): 1.28 min.

This is employed for the next step without further purification.

4.4 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]-pyridin-5-yl)pyrido[3,2-d]pyrimidine

0.20 g of6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one and139 μl of 1,2,3,4-tetrahydroisoquinoline are suspended in 10 ml ofacetonitrile and 1 ml of dimethylformamide in a flask. 0.65 g of(benzotriazol-1-yloxy)tris-(dimethylamino)phosphoniumhexafluorophosphate, 255 μl of 1,8-diaza-bicyclo[5.4.0]undec-7-ene aresubsequently added, and the mixture is heated at 60° C. under nitrogenuntil the reaction has proceeded to completion (HPLC check, about 5hours). A precipitate precipitates out of the reaction solution. This isfiltered off, rinsed with water and dried, giving 0.20 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine(“A6”) as white solid (yield 65%, content 94%); MS-FAB (M+H⁺)=379.1;R_(f) (polar method): 1.86 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.87 (s, 1H), 9.10 (d, J=2.0, 1H),8.75 (d, J=1.8, 1H), 8.56 (s, 1H), 8.49 (d, J=8.9, 1H), 8.20 (d, J=8.9,1H), 7.61-7.56 (m, 1H), 7.32-7.18 (m, 4H), 6.63 (dd, J=3.3, 1.7, 1H),4.69 (s, 3H), 3.16 (s, 2H), 2.07 (s, 1H).

EXAMPLE 5 Preparation of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine(“A7”) Preparation of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine

0.20 g of6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-3H-pyrido[3,2-d]pyrimidin-4-one and0.22 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are suspended in10 ml of acetonitrile and 1 ml of dimethylformamide in a flask. 0.65 gof (benzo-triazol-1-yloxy)tris-(dimethylamino)phosphoniumhexafluorophosphate, 255 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene aresubsequently added, and the mixture is heated at 60° C. under nitrogenuntil the reaction has proceeded to completion (HPLC check, about 5hours). A precipitate precipitates out of the reaction solution. This isfiltered off, rinsed with water and dried, giving 0.17 g of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyri-din-5-yl)pyrido[3,2-d]pyrimidine(“A7”) as white solid (yield 50%, content 97%); MS-FAB (M+H⁺)=439; R_(f)(polar method): 1.68 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.87 (s, 1H), 9.10 (d, J=1.9, 1H),8.75 (d, J=1.7, 1H), 8.55 (s, 1H), 8.49 (d, J=8.9, 1H), 8.19 (d,J=8.8.1H), 7.61-7.55 (m, 1H), 6.89 (s, 1H), 6.85 (s, 1H), 6.61 (dd,J=3.3, 1.8, 1H), 3.75 (d, J=6.8, 6H), 3.08 (s, 2H), 2.84-2.70 (m, 2H),2.66 (dd, J=26.0, 24.3, 2H).

EXAMPLE 6 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo-[4,5-b]pyridin-6-yl)quinazoline(“A4”) 6.1 Preparation of6-bromo-2-methyl-1-(2-trimethylsilanylethoxymethyl)-1H-imidazo[4,5-b]pyridine

8.00 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine in 275 ml oftetrahydro-furan is initially introduced in a flask. 1.66 g of sodiumhydride (60% in paraffin oil) are added in portions with ice-cooling.7.00 ml of 2-trimethylsilylethoxy-methyl chloride is subsequently addeddropwise at about −30° C., and the mixture is stirred at 25° C. undernitrogen until the pyridine has reacted completely (HPLC check, about 4hours). The cooled reaction solution is added to about 200 ml of waterand extracted three times with EA. The combined organic phases are driedover sodium sulfate and purified by means of column chromatography(gradient heptane: EA 5-100% in 34 min.), giving 5.30 g of6-bromo-2-methyl-1-(2-trimethylsilanylethoxymethyl)-1H-imidazo[4,5-b]pyridineas white solid (yield 40%, content 99%); MS-FAB (M+H⁺)=343.1; R_(f)(polar method): 2.59 min.

6.2 Preparation of2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridine

4.00 g of6-bromo-2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo-[4,5-b]pyridine,4.45 g of bis(pinacolato)diboron, 3.44 g of potassium acetate and 1.71 gof PdCl₂(dppf) in 35 ml of dimethyl sulfoxide are heated at 90° C. undernitrogen in a flask until the reaction is complete (HPLC check, about 2hours). The cooled reaction solution is diluted with EA and washed 3times with water. The organic phase is dried over sodium sulfate andpurified by means of column filtration (eluent: EA), giving 3.40 g of2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridineas dark-brown solid (yield 68%, content 92%); MS-FAB (M+H⁺)=390.2; R_(f)(polar method): 2.69 min.

This is employed for the next step without further purification.

6.3 Preparation of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline

0.75 g of 4-chloro-6-iodoquinazoline, 0.45 g of1,2,3,4-tetrahydroisoquinoline and 0.63 ml of triethylamine in 6.0 ml ofdioxane are heated at 80° C. in a flask until the quinazoline hasreacted completely (HPLC check, about 3 hours). The cooled reactionsolution is evaporated to dryness in a rotary evaporator. The residue ispurified by means of column chromatography (gradient heptane: EA 10-100%in 20 min.), giving 0.87 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline as yellowish solid(yield 90%, content 92%); MS-FAB (M+H⁺)=388.0; R_(f) (polar method):1.84 min.

6.4 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline

0.87 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline, 0.96 gof2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine,0.52 g of sodium hydrogencarbonate and 0.29 g of Pd(PPh₃)₂Cl₂ in 17 mlof dioxane and 2 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 3 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient EA: methanol 0-30% in 20 min),giving 0.85 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazolineas white powder (yield 60%, content 86%); MS-FAB (M+H⁺)=523.2; R_(f)(polar method): 2.12 min.

6.5 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline

0.70 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazolineand 825 μl of trifluoroacetic acid in 8 ml of dichloromethane arestirred at 25° C. in a flask until the reaction is complete (HPLC check,about 120 hours). The cooled reaction solution is diluted withdichloromethane and washed with sodium hydrogen-carbonate solution. Theorganic phase is dried over sodium sulfate and purified by means ofcolumn chromatography (gradient EA: methanol 0-30% in 13 min), giving0.19 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline(“A4”) as white solid (yield 36%, content 97%); MS-FAB (M+H⁺)=393.1;R_(f) (polar method): 1.39 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.64 (s, 1H), 8.29 (d, J=1.8, 2H),8.22 (dd, J=8.7, 1.9, 2H), 7.91 (d, J=8.7, 1H), 7.36-7.18 (m, 4H), 5.75(s, 1H), 5.01 (s, 2H), 4.11 (t, J=5.8, 2H), 3.18-3.08 (m, 2H), 2.56 (s,3H).

EXAMPLE 7 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(2-methyl-3H-imidazo[4,5-b]-pyridin-6-yl)quinazoline(“A5”) 7.1 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline

1.30 g of 4-chloro-6-iodoquinazoline, 1.50 ml of1,2,3,4-tetrahydroquinoline in 10 ml of dioxane are heated at 110° C. ina flask until the quinazoline has reacted completely (HPLC check, about3 hours). The cooled reaction solution is diluted with EA and washed 3times with 5% citric acid. The organic phase is dried over sodiumsulfate and purified by means of column chromatography (gradientheptane: EA 0-100% in 18 min.), giving 1.27 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline as yellowish solid(yield 81%, content 99%); MS-FAB (M+H⁺)=388.0; R_(f) (polar method):2.89 min.

7.2 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazoline

0.25 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-iodoquinazoline, 0.30 g of2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine,0.16 g of sodium hydrogencarbonate and 0.09 g of Pd(PPh₃)₂Cl₂ in 5.00 mlof dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 5 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient EA: methanol 0-40% in 20 min),giving 0.19 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazolineas white powder (yield 50%, content 94%); MS-FAB (M+H⁺)=523.2; R_(f)(polar method): 2.54 min.

7.3 Preparation of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline

0.19 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-[2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazolineand 200 μl of trifluoro-acetic acid in 2 ml of dichloromethane arestirred at 25° C. in a flask until the reaction is complete (HPLC check,about 48 hours). The cooled reaction solution is evaporated to drynessin a rotary evaporator. The residue is purified by means of preparativeHPLC (gradient water:acetonitrile 1-50% in 14 min.), giving 0.03 g of4-(3,4-dihydro-2H-quinolin-1-yl)-6-(2-methyl-3H-imidazo-[4,5-b]pyridin-6-yl)quinazoline(“A5”) as white solid (yield 23%, content 99%); MS-FAB (M+H⁺)=393.1;R_(f) (polar method): 1.41 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.86 (s, 1H), 8.18-8.13 (m, 3H), 7.94(d, J=8.6, 1H), 7.72 (d, J=22.6, 1H), 7.59 (s, 1H), 7.35 (d, J=7.0, 1H),7.12 (t, J=7.6, 1H), 7.05 (t, J=7.4, 1H), 6.76 (d, J=7.6, 1H), 4.05 (t,J=6.5, 2H), 2.89 (t, J=6.5, 2H), 2.55 (s, 3H), 2.10-2.04 (m, 2H).

EXAMPLE 8 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo-[4,5-b]pyridin-6-yl)pyrido[3,2-d]pyrimidine(“A8”) 8.1 Preparation of methyl3-amino-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridine-2-carboxylate

1.00 g of methyl 3-amino-6-bromopyridine-2-carboxylate, 2.00 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine,1.00 g of sodium hydrogencarbonate and 0.30 g of PdCl₂(PPh₃)₂ in 20 mlof dioxane and 2 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 7 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient EA: methanol 0-20% in 30 min),giving 1.00 g of methyl3-amino-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo-[4,5-b]pyridin-6-yl]pyridine-2-carboxylateas white solid (yield 60%, content 98%); MS-FAB (M+H⁺)=414.2; R_(f)(polar method): 2.24 min.

8.2 Preparation of6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3H-pyrido[3,2-d]pyrimidin-4-one

1.00 g of methyl3-amino-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridine-2-carboxylatein 16 ml of formamide are heated at 130° C. under nitrogen in a flaskuntil the reaction is complete (HPLC check, about 48 hours). The excessformamide is distilled off (120° C., 1 mbar). The residue is dissolvedin dichloromethane, washed with water, dried and purified by means ofcolumn chromatography (gradient EA: methanol 0-50% in 15 min), giving0.40 g of6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3H-pyrido[3,2-d]pyrimidin-4-oneas reddish solid (yield 36%, content 95%); MS-FAB (M+H⁺)=409.1; R_(f)(polar method): 2.01 min.

8.3 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridine

0.20 g of6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyri-din-6-yl]-3H-pyrido[3,2-d]pyrimidin-4-oneand 89 μl of 1,2,3,4-tetrahydroisoquinoline are suspended in 6.00 ml ofacetonitrile and 0.50 ml of dimethyl-formamide in a flask. 0.43 g of(benzotriazol-1-yloxy)tris-(dimethylamino)phosphoniumhexafluorophosphate, 164 μl of 1,8-diazabicyclo[5.4.0]undec-7-ene aresubsequently added, and the mixture is stirred at 25° C. under nitrogenuntil the reaction has proceeded to completion (HPLC check, about 4hours). A precipitate precipitates out of the reaction solution. This isfiltered off, rinsed with water and dried, giving 0.13 g of4-(3,4-dihydro-1H-zisoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridineas white solid (yield 50%, content 99%); MS-FAB (M+H⁺)=524.2; R_(f)(polar method): 2.53 min.

8.4 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrido[3,2-d]pyrimidine

0.12 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]pyridineand 141 μl of trifluoroacetic acid in 1.50 ml of dichloromethane arestirred at 25° C. in a flask until the reaction is complete (HPLC check,about 24 hours). The cooled reaction solution is diluted withdichloromethane and washed with sodium hydrogencarbonate solution. Theorganic phase is dried over sodium sulfate, evaporated in a rotaryevaporator, and the residue is suspended in acetonitrile. The solid isfiltered off with suction and dried, giving 0.02 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-pyrido[3,2-d]pyrimidine(“A8”) as white solid (yield 24%, content 99%); MS-FAB (M+H⁺)=394.1;R_(f) (polar method): 1.47 min;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 9.50 (dd, J=26.0, 1.7, 1H), 9.13-8.99(m, 2H), 8.89 (d, J=8.9, 1H), 8.48 (d, J=8.9, 1H), 7.51-7.38 (m, 1H),7.38-7.17 (m, 3H), 6.31 (s, 1H), 5.50 (s, 1H), 5.18 (t, J=5.7, 1H), 4.57(t, J=5.8, 1H), 3.39 (t, J=5.7, 1H), 3.21 (t, J=5.6, 1H), 2.95 (d,J=3.8, 3H).

EXAMPLE 9 Preparation of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrido[3,2-d]pyrimidine(“A9”) 9.1 Preparation of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridine

0.35 g of6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]-3H-pyrido[3,2-d]pyrimidin-4-oneand 0.18 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are suspendedin 5 ml of acetonitrile and 1 ml of dimethylformamide in a flask. 0.68 gof (benzotriazol-1-yloxy)tris-(dimethyl-amino)phosphoniumhexafluorophosphate, 264 μl of 1,8-diazabicyclo[5.4.0]-undec-7-ene aresubsequently added, and the mixture is stirred at 25° C. under nitrogenuntil the reaction has proceeded to completion (HPLC check, about 48hours). A precipitate precipitates out of the reaction solution. This isfiltered off and purified by means of column chromatography (gradientEA: methanol 0-40% in 20 min), giving 0.07 g of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridineas white solid (yield 15%, content 93%); MS-FAB (M+H⁺)=584.2; R_(f)(polar method): 2.26 min.

9.2 Preparation of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrido[3,2-d]pyrimidine

0.07 g of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridineand 141 μl of trifluoro-acetic acid in 1 ml of dichloromethane arestirred at 25° C. in a flask until the reaction is complete (HPLC check,about 24 hours). The cooled reaction solution is evaporated to drynessin a rotary evaporator. The residue is purified by means of prep. HPLC(gradient water:acetonitrile 1-50% in 14 min.), giving 0.01 g of4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrido-[3,2-d]pyrimidine(“A9”) as white solid (yield 30%, content 99%); MS-FAB (M+H⁺)=454.2R_(f) (polar method): 1.41 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.37 (s, 1H), 8.90 (s, 1H), 8.86 (s,1H), 8.73 (d, J=8.9, 1H), 8.41 (d, J=8.9, 1H), 6.90 (s, 1H), 6.86 (s,1H), 3.77 (s, 6H), 3.17 (s, 2H), 2.88 (s, 3H), 1.21 (t, J=7.1, 2H).

EXAMPLE 10 Preparation of4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline(“A11”) 10.1 Preparation of6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-quinazoline

0.75 g of 4-chloro-6-iodoquinazoline, 0.58 g of7-methoxy-1,2,3,4-tetrahydro-isoquinoline and 0.64 ml of triethylaminein 5 ml of dioxane are heated at 80° C. in a flask until the quinazolinehas reacted completely (HPLC check, about 2 hours). The cooled reactionsolution is diluted with EA and washed 3 times with water. The organicphase is dried over sodium sulfate and purified by means of columnchromatography (gradient heptane: EA 5-100% in 22 min.), giving 0.60 gof 6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)quinazoline asyellowish solid (yield 57%, content 93%); MS-FAB (M+H⁺)=418.0; R_(f)(polar method): 1.87 min.

10.2 Preparation of4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo]4,5-b]pyridin-6-yl]quinazoline

0.20 g of6-iodo-4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)quinazoline, 0.28 gof5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine,0.11 g of sodium hydrogencarbonate and 0.03 g of Pd(PPh₃)₂Cl₂ in 5.00 mlof dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 5 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient EA: methanol 5-30% in 13 min),giving 0.20 g of4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-[(2-trimethylsilanylethoxymethyl)-3H-imidazo]4,5-b]pyridin-6-yl]quinazolineas white powder (yield 64%, content 79%); MS-FAB (M+H⁺)=553.3; R_(f)(polar method): 2.14 min.

10.3 Preparation of4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline

0.19 g of4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo]4,5-b]pyridin-6-yl]quinazolineand 175 μl of trifluoroacetic acid in 2 ml of dichloromethane arestirred at 25° C. in a flask until the reaction is complete (HPLC check,about 72 hours). The cooled reaction solution is evaporated to drynessin a rotary evaporator. The residue is purified by means of preparativeHPLC. (gradient water:acetonitrile 1-40% in 14 min.), giving 0.02 g of4-(7-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-[(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline(“A11”) as white solid (yield 21%, content 99%); MS-FAB (M+H⁺)=423.1;R_(f) (polar method): 1.38 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.12 (d, J=1.7, 1H), 8.94 (s, 1H),8.73 (d, J=1.8, 1H), 8.68 (s, 1H), 8.48 (dd, J=8.8, 1.6, 1H), 8.05 (d,J=8.7.1H), 7.39 (s, 1H), 7.31 (d, J=6.1, 3H), 5.45 (s, 2H), 4.49 (s,2H), 3.26 (q, J=7.6, 2H), 3.19 (t, J=5.3, 2H), 1.52 (t, J=7.6, 3H).

EXAMPLE 11 Preparation of4-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazolin-4-yl]-3,4-dihydro-2H-benzo-1,4-oxazine(“A12”) 11.1 Preparation of4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine

0.75 g of 4-chloro-6-iodoquinazoline, 0.39 g of3,4-dihydro-2H-benzo-1,4-oxazine and 0.50 ml of triethylamine in 5 ml ofdioxane are heated at 80° C. in a flask until the quinazoline hasreacted completely (HPLC check, about 24 hours). The cooled reactionsolution is evaporated to dryness. The residue is washed by stirringwith EA and filtered off with suction, giving 0.35 g of4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine as yellowishsolid (yield 40%, content 96%); MS-FAB (M+H⁺)=390.0; R_(f) (polarmethod): 2.36 min.

11.2 Preparation of4-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazolin-4-yl}-3,4-dihydro-2H-benzo[-1,4-oxazine

0.20 g of 4-(6-iodoquinazolin-4-yl)-3,4-dihydro-2H-benzo-1,4-oxazine,0.32 g of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine,0.12 g of sodium hydrogencarbonate and 0.03 g of Pd(PPh₃)₂Cl₂ in 5.00 mlof dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 4 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient EA: methanol 0-20% in 15 min),giving 0.23 g of4-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo-[4,5-b]pyridin-6-yl]quinazolin-4-yl}-3,4-dihydro-2H-benzo-[1,4-oxazineas white powder (yield 78%, content 90%); MS-FAB (M+H⁺)=525.2; R_(f)(polar method): 2.51 min.

11.3 Preparation of4-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazolin-4-yl]-3,4-dihydro-2H-benzo-1,4-oxazine

0.20 g of4-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]-pyridin-6-yl]quinazolin-4-yl}-3,4-dihydro-2H-benzo-[1,4-oxazineand 211 μl of trifluoroacetic acid in 2 ml of dichloromethane arestirred at 25° C. in a flask until the reaction is complete (HPLC check,about 72 hours). The cooled reaction solution is evaporated to drynessin a rotary evaporator. The residue is purified by means of preparativeHPLC (gradient water:acetonitrile 1-40% in 16 min.), giving 0.03 g of4-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazolin-4-yl]-3,4-dihydro-2H-benzo-1,4-oxazine(“A12”) as white solid (yield 22%, content 100%); MS-FAB (M+H⁺)=395.1;R_(f) (polar method): 1.43 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.14 (s, 1H), 8.62 (d, J=1.9, 1H),8.43 (dd, J=8.8, 1.9, 1H), 8.28 (d, J=1.9, 1H), 8.22 (d, J=1.6, 1H),8.07 (d, J=8.8, 1H), 7.32 (dd, J=8.2, 1.2, 1H), 7.25 (ddd, J=8.5, 7.4,1.4, 1H), 7.07 (dd, J=8.3, 1.3, 1H), 6.87-6.80 (m, 1H), 4.56 (s, 4H),2.81 (s, 3H).

EXAMPLE 12 Preparation of1-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazolin-4-yl]-2,3-dihydro-1H-quinolin-4-one(“A13”) 12.1 Preparation of1-(6-iodoquinazolin-4-yl)-2,3,4a,8a-tetrahydro-1H-quinolin-4-one

0.75 g of 4-chloro-6-iodoquinazoline, 0.51 g of2,3,4a,8a-tetrahydro-1H-quinolin-4-one and 0.96 ml of triethylamine in 5ml of dioxane are heated at 80° C. in a flask until the quinazoline hasreacted completely (HPLC check, about 24 hours). The cooled reactionsolution is diluted with EA and washed 3 times with water. The organicphase is dried over sodium sulfate and purified by means of columnchromatography (gradient heptane: EA 5-100% in 16 min.), giving 0.40 gof 1-(6-iodoquinazolin-4-yl)-2,3,4a,8a-tetrahydro-1H-quinolin-4-one asyellowish solid (yield 40%, content 91%); MS-FAB (M+H⁺)=402.0; R_(f)(polar method): 2.20 min.

12.2 Preparation of1-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridin-6-yl]quinazolin-4-yl}-2,3-dihydro-1H-quinolin-4-one

0.25 g of1-(6-iodoquinazolin-4-yl)-2,3,4a,8a-tetrahydro-1H-quinolin-4-one, 0.26 gof5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine,0.13 g of sodium hydrogencarbonate and 0.04 g of Pd(PPh₃)₂Cl₂ in 5.00 mlof dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 4 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient EA: methanol 0-30% in 14 min),giving 0.25 g of1-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo-[4,5-b]pyridin-6-yl]quinazolin-4-yl}-2,3-dihydro-1H-quinolin-4-oneas white powder (yield 73%, content 89%); MS-FAB (M+H⁺)=237.2; R_(f)(polar method): 2.50 min.

12.3 Preparation of1-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazolin-4-yl]-2,3-dihydro-1H-quinolin-4-one

0.25 g of1-{6-[2-methyl-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]-pyridin-6-yl]quinazolin-4-yl}-2,3-dihydro-1H-quinolin-4-oneand 255 μl of tri-fluoroacetic acid in 2 ml of dichloromethane arestirred at 25° C. in a flask until the reaction is complete (HPLC check,about 72 hours). The cooled reaction solution is evaporated to drynessin a rotary evaporator. The residue is purified by means of preparativeHPLC (gradient water:acetonitrile 1-50% in 16 min.), giving 0.04 g of1-[6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-quinazolin-4-yl]-2,3-dihydro-1H-quinolin-4-one(“A13”) as white solid (yield 23%, content 99%); MS-FAB (M+H⁺)=407.1;R_(f) (polar method): 1.50 min;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 9.34 (s, 1H), 8.55 (d, J=2.0, 1H),8.51 (dd, J=8.8, 1.9, 1H), 8.22 (d, J=2.0, 1H), 8.18 (d, J=8.8, 1H),8.16-8.09 (m, 1H), 8.00 (d, J=1.7, 1H), 7.56 (dd, J=6.7, 2.9, 2H),7.48-7.40 (m, 1H), 4.91 (s, 2H), 3.12 (dd, J=13.2, 6.4, 2H), 2.88 (s,3H).

EXAMPLE 13 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-ethyl-3H-imidazo-[4,5-b]pyridin-6-yl)quinazoline(“A10”) 13.1 Preparation of 6-bromo-2-ethyl-3H-imidazo[4,5-b]pyridine

4 g of 5-bromopyridine-2,3-diamine in 40 ml of propionic acid is heatedat 140° C. in a flask until the diamine has reacted completely (HPLCcheck, about 24 hours). The cooled reaction solution is evaporated todryness. The residue is suspended in water, filtered off with suctionand purified by means of column chromatography (gradient EA: methanol5-40% in 30 min), giving 2.25 g of6-bromo-2-ethyl-3H-imidazo[4,5-b]pyridine as yellowish solid (yield 45%,content 98%); MS-FAB (M+H⁺)=228.0; R_(f) (polar method): 1.27 min.

13.2 Preparation of2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine

2.50 g of 6-bromo-2-ethyl-3H-imidazo[4,5-b]pyridine, 4.21 g ofbis(pinacolato)-diboron, 3.25 g of potassium acetate and 1.61 g ofPdCl₂(dppf) in 30 ml of dimethyl sulfoxide are heated at 90° C. undernitrogen in a flask until the reaction is complete (HPLC check, about 10hours). The cooled reaction solution is diluted with EA and washed 3times with water. The organic phase is dried over sodium sulfate, giving0.35 g of2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2-trimethylsilanylethoxymethyl)-3H-imidazo[4,5-b]pyridineas dark-brown solid (yield 11%, content 99%). This is employed for thenext step without further purification.

13.3 Preparation of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline

0.25 g of 4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-iodoquinazoline, 0.35 gof2-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine,0.52 g of sodium hydrogencarbonate and 0.29 g of Pd(PPh₃)₂Cl₂ in 17 mlof dioxane and 2 ml of water are heated at 90° C. under nitrogen in aflask until the reaction is complete (HPLC check, about 3 hours). Thecooled reaction solution is diluted with EA and washed 3 times withwater. The organic phase is dried over sodium sulfate and purified bymeans of column chromatography (gradient EA: methanol 0-45% in 16 min),giving 0.05 g of4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline(“A10”) as white powder (yield 92%, content 94%); MS-FAB (M+H⁺)=407.2;R_(f) (polar method): 1.40 min;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 9.12 (d, J=1.7, 1H), 8.94 (s, 1H),8.73 (d, J=1.8, 1H), 8.68 (s, 1H), 8.48 (dd, J=8.8, 1.6, 1H), 8.05 (d,J=8.7, 1H), 7.39 (s, 1H), 7.31 (d, J=6.1, 3H), 5.45 (s, 2H), 4.49 (s,2H), 3.26 (q, J=7.6, 2H), 3.19 (t, J=5.3, 2H), 1.52 (t, J=7.6, 3H).

DNA-PK and PI3 Kinase Inhibition

TABLE 1 Compound DNA-PK PI3K (cellular) No. IC50 IC50 “A1” A B “A2” A B“A3” A B “A4” A A “A5” A B “A6” A B “A7” A “A8” A A “A9” A A “A10” A A“A11” A A “A12” A B “A13” A B IC₅₀: 1 nM-0.1 μM = A 0.1 μM-10 μM = B >10μM = C

The following examples relate to medicaments:

EXAMPLE A Injection vials

A solution of 100 g of an active compound of the formula I and 5 g ofdi-sodium hydrogenphosphate in 3 I of bidistilled water is adjusted topH 6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activecompound.

EXAMPLE B Suppositories

A mixture of 20 g of an active compound of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of active compound.

EXAMPLE C Solution

A solution is prepared from 1 g of an active compound of the formula I,9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis pressed in a conventional manner to give tablets in such a way thateach tablet contains 10 mg of active compound.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active compound of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active compound.

EXAMPLE H Ampoules

A solution of 1 kg of active compound of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active compound.

1. Compounds of the formula I

in which A¹ denotes N or CR¹, A² denotes N or CR², A³, A⁴, A⁵, A⁶ each,independently of one another, denote N or CR³, X is absent or denotesunbranched or branched alkylene having 1-10 C atoms, in which 1-7 Hatoms may be replaced by OH, F and/or Cl, and/or in which one or twonon-adjacent CH and/or CH₂ groups may be replaced by O, N, NH, NA′, CO,S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/or CH═CH groups, orcycloalkylene having 3-7 C atoms, L² is absent or denotes unbranched orbranched alkylene having 1-10 C atoms, in which 1-7 H atoms may bereplaced by OH, F and/or Cl, and/or in which one or two non-adjacent CHand/or CH₂ groups may be replaced by O, N, NH, NA′, CO, S, SO, SO₂, OCO,NHCONH, NHCO, NHSO₂, COO, CONH and/or CH═CH groups, or cycloalkylenehaving 3-7 C atoms, with the proviso that X and L² cannot be absentsimultaneously, R denotes H or unbranched or branched alkyl having 1-10C atoms, in which 1-7 H atoms may be replaced by F and/or Cl and/or inwhich one or two non-adjacent CH and/or CH₂ groups may be replaced by O,N, NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/orCH═CH groups, or cyclic alkyl having 3-7 C atoms, R¹ denotes H orunbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atomsmay be replaced by F and/or Cl and/or in which one or two non-adjacentCH and/or CH₂ groups may be replaced by O, N, NH, NA′, CO, S, SO, SO₂,OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/or CH═CH groups, or cyclic alkylhaving 3-7 C atoms, R² denotes H or unbranched or branched alkyl having1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or Cl and/orin which one or two non-adjacent CH and/or CH₂ groups may be replaced byO, N, NH, NA′, CO, S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONHand/or CH═CH groups,  or cyclic alkyl having 3-7 C atoms, R³ denotes Hor unbranched or branched alkyl having 1-10 C atoms, in which 1-7 Hatoms may be replaced by F and/or Cl and/or in which one or twonon-adjacent CH and/or CH₂ groups may be replaced by O, N, NH, NA′, CO,S, SO, SO₂, OCO, NHCONH, NHCO, NHSO₂, COO, CONH and/or CH═CH groups, orcyclic alkyl having 3-7 C atoms, A′ in each case, independently of oneanother, denotes unbranched or branched alkyl having 1-10 C atoms, inwhich 1-7 H atoms may be replaced by F and/or Cl, and/or in which one ortwo non-adjacent CH and/or CH₂ groups may be replaced by O, N, NH, NA,S, SO, SO₂ and/or CH═CH groups, or cyclic alkyl having 3-7 C atoms, Adenotes alkyl having 1, 2, 3 or 4 C atoms, and pharmaceutically usablesalts, tautomers and stereoisomers thereof, including mixtures thereofin all ratios.
 2. Compounds according to claim 1 in which A³, A⁴, A⁵, A⁶denote CR³, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 3.Compounds according to claim 1 in which X is absent or denotesunbranched or branched alkylene having 1-4 C atoms, and in which one CH₂group may be replaced by O, NH, CO or SO₂, and pharmaceutically usablesalts, tautomers and stereoisomers thereof, including mixtures thereofin all ratios.
 4. Compounds according to claim 1 in which L² is absentor denote unbranched or branched alkylene having 1-4 C atoms, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 5. Compounds according toclaim 1 in which R denotes H or unbranched or branched alkyl having 1-4C atoms, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 6. Compoundsaccording to claim 1 in which R¹ denotes H, and pharmaceutically usablesalts, tautomers and stereoisomers thereof, including mixtures thereofin all ratios.
 7. Compounds according to claim 1 in which R² denotes H,and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 8. Compounds according toclaim 1 in which R³ denotes H or unbranched or branched alkyl having 1-4C atoms and in which one CH₂ group may be replaced by O, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 9. Compounds according toclaim 1 in which A¹ denotes N or CR¹, A² denotes N or CR², A³, A⁴, A⁵,A6 denote CR³, X is absent or denotes unbranched or branched alkylenehaving 1-4 C atoms,  and in which one CH₂ group may be replaced by O,NH, CO or SO₂, L² is absent or denotes unbranched or branched alkylenehaving 1-4 C atoms, R denotes H or unbranched or branched alkyl having1-4 C atoms, R¹ denotes H, R² denotes H, R³ denotes H or unbranched orbranched alkyl having 1-4 C atoms and in which one CH₂ group may bereplaced by O, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 10.Compounds according to claim 1, selected from the group Compound No.Name “A1” 4-(2,3-Dihydroindol-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazoline “A2” 4-(1,3-Dihydroisoindol-2-yl)-6-(1H-pyrrolo[2,3-b]-pyridin-5-yl)quinazoline “A3”4-(3,4-Dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]-pyridin-5-yl)quinazoline “A4”4-(3,4-Dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline “A5”4-(3,4-Dihydro-2H-quinolin-1-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline “A6”4-(3,4-Dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo-[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine “A7”4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrido[3,2-d]pyrimidine “A8”4-(3,4-Dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrido[3,2-d]pyrimidine “A9”4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)pyrido[3,2- d]pyrimidine “A10”4-(3,4-Dihydro-1H-isoquinolin-2-yl)-6-(2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline “A11”4-(7-Methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)quinazoline “A12”4-[6-(2-Methyl-3H-imidazo[4,5-b]pyridin-6-yl)-quinazolin-4-yl]-3,4-dihydro-2H-benzo-1,4-oxazine “A13”1-[6-(2-Methyl-3H-imidazo[4,5-b]pyridin-6-yl)-quinazolin-4-yl]-2,3-dihydro-1H-quinolin-4-one

and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 11. Process for thepreparation of compounds of the formula I according to claim 1 andpharmaceutically usable salts, tautomers and stereoisomers thereof,characterised in that a) a compound of the formula II

in which R, A¹ and A² have the meanings indicated in claim 1, is reactedwith a compound of the formula III

in which X, L², A³, A⁴, A⁵ and A⁶ have the meanings indicated in claim1, or b) a compound of the formula IV

in which R and A² have the meanings indicated in claim 1 and L denotes aboronic acid or boronic acid ester radical, is reacted with a compoundof the formula V

in which X, L², A¹, A³, A⁴, A⁵ and A⁶ have the meanings indicated inclaim 1, and/or a base or acid of the formula I is converted into one ofits salts.
 12. Medicaments comprising at least one compound of theformula I according to claim 1 and/or pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.
 13. A method for thetreatment of autoimmune diseases, inflammatory diseases, cardiovasculardiseases, neurodegenerative diseases, allergy, asthma, pancreatitis,multiorgan failure, kidney diseases, blood platelet aggregation, cancer,sperm motility, transplant rejection, graft rejection and lung injuries,comprising administering a compound of formula I of claim
 1. 14. Set(kit) consisting of separate packs of (a) an effective amount of acompound of the formula I according to claim 1, and/or pharmaceuticallyusable salts and stereoisomers thereof, including mixtures thereof inall ratios, and (b) an effective amount of a further medicament activecompound.